Malignant gliomas are among the most deadly of human cancers, with most patients succumbing to the disease within a year of diagnosis. Recently, tumor cells with properties of stem cells have been identified in malignant gliomas. These cells share properties with normal neural stem cells, including multipotency and the capacity for self-renewal. Experimental evidence suggests that this relatively small and quiescent component of the overall tumor is responsible for tumor growth and maintenance and may account for tumor recurrence despite conventional therapies. The identification of these cells has spurred intense interest in understanding their relationship to normal CMS stem cells and the molecular mechanisms that regulate their biological behavior. Such knowledge promises to open entirely new avenues of treatment for glioma patients by targeting these cells and the signaling pathways that regulate their survival, growth and differentiation. Emerging data indicate that members of the transforming growth factor-beta (TGF-beta) superfamily regulate thetumorigenic properties of brain tumor stem cells, and TGF-beta has been implicated in the pathogenesis and progression of human gliomas. TGF-beta signaling has also recently been shown to regulate normal neural stem cells. By conditional activation of oncogenic k-ras and deletion of the TGF-(beta type II receptor in the mouse brain, we have developed a novel model that provides insight into the role of Ras and TGF-beta signaling in gliomagenesis and the regulation of neural stem cells. In the experiments proposed in Specific Aim 1 of this Mentored Career Development Award application, the role of TGF-beta in the pathogenesis of glioma will be investigated in clinically relevant mouse models of human glioma. In Specific Aim 2, the mechanisms by which the Ras and TGF-beta signaling pathways regulate the proliferation, differentiation and migration of normal and transformed neural stem cells will be examined. In Specific Aim 3, we will test, in orthotopic transplant experiments, whether stem cells with genetic alterations that are common in human glioma are capable of tumor formation and whether TGF-beta signaling modulates this process. A comprehensive career development plan for the principal investigator, Dr. Ty Abel, a physician-scientist with clinical neuropathology training, is described. The pursuit of the specific aims will teach Dr. Abel new investigative skills, including glioma modeling and stem cell culture, and will facilitate his transition to independent investigator in brain cancer research. Relevance: Malignant gliomas are aggressive, nearly uniformly fatal cancers. A better understanding of the molecular pathways, including the role of stem cells, regulating the development and progression of glioma may lead to novel and more effective treatments.